1. Field of Invention
The present invention relates to a medicine, particularly to a method for preparing medicine, and more particularly to a method for preparing ulipristal acetate with an anti-progesterone and anti-glucocorticoid function and to a key intermediate and a preparing method therefor.
2. Description of Related Arts
Ulipristal acetate (a compound I; chemical name: 17α-acetoxyl-11β-(4-N,N-dimethylamino-phenyl)-19-norpregna-4,9-diene-3,20-dione) is a strong anti-progesterone and anti-glucocorticoid medicine. A constitutional formula of the Ulipristal acetate is as follows:

The Ulipristal acetate has been approved to be sold in Europe and America for being used within five days after unprotected sex and a known or suspected contraceptive failure, the Ulipristal acetate is an effective and safe emergency contraceptive.
Related reports of methods for preparing the Ulipristal acetate are as follows.
1. A method disclosed in the U.S. Pat. No. 4,954,490, (as illustrated in the equation I)
The method utilizes 3-methoxyl-19-norpregna-1,3,5(10),17(20)-tetraene as a starting material, and after an addition reaction, oxidation, reduction, hydrolysis and an addition-elimination action, 17α-hydroxyl-19-norpregna-4,9-diene-3,20-dione (a compound V2) is obtained by the oxidation, then the Ulipristal acetate (the compound I) is obtained by a total of ten reactions comprising ethylene glycol condensation, m-chloroperoxy benzoic acid epoxidation, Grignard addition, acid hydrolysis and acetylation, and a product with a melting point of 118˜121° C. is obtained by water/methanol recrystallization. The method is not adaptable to an industrialized production because the steps of the method are too many, the starting material is not easy to be obtained, reaction conditions are complex, intermediates need to be chromatography purified, a its total yield is only 0.62%, costs are very high and the product is not stable enough to be utilized in the medicine;
the equation I:

2. Another method disclosed in the U.S. Pat. No. 5,929,262 (as illustrated in the equation II)
the equation II:

the method utilizes 3,3-ethylendioxyl-17β-cyano-19-norpregna-5(10),9(11)-diene-17α-alcohol (a compound III) as the starting material, and 17α-hydroxy is protected by dimethyl chloromethyl silicane, the starting material is acid hydrolyzed after a reaction with a DBB/Li reagent at a low temperature of −70° C., then diketal is obtained by the ethylene glycol condensation reaction, a desired product is obtained by the epoxidation reaction, the Grignard reaction, the acid hydrolysis reaction and the acetylation reaction, and a yellow product with a melting point of 183˜185° C. is obtained by isopropanol, ethyl acetate and ethyl ether crystallization treatments. The method also does not adapt to the industrialized production because a cost of the starting material and DBB are very high, the reaction conditions are strict, an ultra low temperature and anhydrous anaerobic reaction are needed, the yield is low (wherein the total yield is only 14%) and the costs are also very high.
3. A third method was disclosed in the PCT application WO2004078709, (as illustrated in the equation III), a desired product is obtained by utilizing 17α-hydroxyl-19-norpregna-4,9(10)-diene-3,17-dione (a compound V2) with the acetylization, 3-carbonyl condensation, the epoxidation and the hydrolysis. A route of synthesis is simple, but the starting material is prepared from a compound VI by hydrolysis under an acidic condition, the total yield is only 11.8% (calculated from the compound VI), and in fact, the steps are much more, the yield is lower and the costs are higher, therefore, the method is not adaptable to the industrialized production;
the equation III:

4. A method was disclosed in the Chinese patent application CN200780021915.9 (as illustrated in the equation IV);
the equation IV:

the method utilizes 3,3-ethylendioxyl-19-norpregna-5 (10),9 (11)-diene-17-one (3-Ethylene Ketal for short, a compound II) as the starting material, the desired product is obtained by a total of nine reactions comprising the acetylene addition reaction, reaction with phenylsulfenyl chloride, the sodium methoxide hydrolysis, the acid hydrolysis, the ethylene glycol condensation, the epoxidation, the Grignard reaction, the acid hydrolysis and the acetylation reaction, solvate-free crystals are obtained after the isopropanol crystallization and being heated by ethanol and water for 14 h at 70° C. The method utilizes acetylene with great danger and the phenylsulfenyl chloride with a stink, wherein the phenylsulfenyl chloride is not stable and not easy to be stored, and impurities produced by decomposition involved in the reactions will lead to the low yield, additionally, the phenylsulfenyl chloride can deeply pollute environments, and new impurities is produced by being heated for a long time at the high temperature in the crystallization reaction, the total yield of the method is 13.8%˜15.8%, the costs are high, therefore, the method is not adaptable to the industrialized production.
In the conventional methods as above, the method 1, 2 and 4 are related to preparation of the compound VI, and the starting material of the method 3 is hydrolyzed from the compound VI.